Project Summary/Abstract Autism Spectrum Disorders (ASDs) are thought to result from in brain synapse dysfunction. Mutations or deletions of the MEF2C gene have been linked recently to several neurodevelopmental disorders, including autism, intellectual disability (ID) and schizophrenia (SCZ). Mef2 transcription factors promote activity- dependent, glutamatergic synapse elimination ? a possible dysregulated process in autism. We find that Mef2c conditional forebrain knockout (Mef2c cKO) mice display behavioral abnormalities similar to the 3 core features used to diagnose autism in humans, including abnormalities in communication, social interaction, and repetitive motor behaviors. Surprisingly, we observed a significant increase in inhibitory (GABAergic) and a decrease in excitatory (glutamatergic) synapse density and strength, which suggests the hypothesis that Mef2c functions as an activity-regulated transcriptional repressor to control the balance of inhibitory and excitatory synapses in developing cortical neurons. Loss of Mef2c repressor function promotes excitatory synapse elimination and increases inhibitory synapse density, which results in numerous behaviors with potential relevance to autism, ID and SCZ. In this revised grant proposal, we seek to extend our extensive preliminary findings to explore the role and regulation of Mef2c in cortical synapse development and in behaviors associated with intellectual and developmental disabilities. Aim 1. In this aim, we will use well-established behavioral assays in the lab to analyze social interaction, communication, repetitive behaviors, reward, anxiety, and learning and memory tests in Mef2c cKO mice. Aim 2. In this aim, we will take a multi-pronged approach in culture and in vivo to analyze the role of Mef2c in the regulation of excitatory and inhibitory synapse density and function. We will test the hypothesis that Mef2c functions cell-autonomously as a transcriptional repressor to regulate glutamatergic synapse elimination and GABAergic synapse formation/stabilization, and it does so in an activity-dependent, homeostatic, negative feedback mechanism that promotes inhibition and reduces excitation. Aim 3. In this aim, we will extend our preliminary findings with HTS-CLIP and RNA-seq to assess the role of Pcdh17, an newly identified common MEF2/FMRP target gene, in Mef2c-induced excitatory synapse elimination and inhibitory synapse formation in cortical pyramidal neurons in culture and in vivo.